Systems, apparatuses, and methods for detecting ectopic electrocardiogram signals during pulsed electric field ablation

ABSTRACT

Systems, apparatus, and methods for ablation therapy are described herein, with a processor for confirming pacing capture or detecting ectopic beats. An apparatus includes a processor for receiving cardiac signal data captured by a set of electrodes, extracting a sliding window of the cardiac signal data, identifying a peak frequency over a subrange of frequencies associated with the extracted sliding window, detecting ectopic activity based at least on a measure of the peak frequency over the subrange of frequencies, in response to detecting ectopic activity, sending an indication of ectopic activity to a signal generator configured to generate pulsed waveforms for cardiac ablation such that the signal generator is deactivated or switched off from generating the pulsed waveforms. An apparatus can further include a processor for confirming pacing capture of the set of pacing pulses based on cardiac signal data.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/573,704, filed on Sep. 17, 2019, now issued as U.S. Pat. No.10,625,080, the entire disclosure of which is incorporated herein byreference in its entirety.

BACKGROUND

Application of brief ultra-short high voltage pulses to tissue maygenerate high electric fields in tissue to generate a local region ofablated tissue by the biophysical mechanism of irreversibleelectroporation.

In cardiac applications, high voltage pulses, however, may causecomplications such as induced arrhythmias (e.g., ventricularfibrillation) if delivered during certain periods of cardiac activity.Accordingly, it can be desirable to delivery high voltage pulses forpulsed electric field ablation in synchrony with the cardiac cycle so asto avoid the risk of such complications,

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of a system, according to embodiments.

FIG. 2 is a schematic cross-sectional illustration of an ablationcatheter and a pacing catheter disposed in a heart, according toembodiments.

FIGS. 3A and 3B are schematic illustrations of a time sequence ofelectrocardiograms and cardiac pacing signals, according to embodiments.

FIG. 4 schematically depicts a device for generating pulsed electricfield ablation, according to embodiments.

FIG. 5 depicts components of a device for detecting cardiac activity,according to embodiments.

FIG. 6 illustrates a method for tissue ablation, according toembodiments.

FIG. 7 illustrates a method for detecting ectopic cardiac activity,according to embodiments.

FIG. 8 illustrates a method for tissue ablation, according toembodiments.

FIG. 9 illustrates a method for detecting ectopic cardiac activity,according to embodiments.

FIG. 10 illustrates a method for detecting ectopic cardiac activity andconfirming pacing capture, according to embodiments.

DETAILED DESCRIPTION

Described herein are systems, devices, and methods for detecting ectopiccardiac activity in connection with delivery of ablation energy totissue such as pulsed electric field ablation. Pulsed electric fieldablation uses ultra-short high-voltage pulses to generate large electricfields at desired regions of interest to generate a local region ofablated tissue via irreversible electroporation. In certainapplications, including cardiac applications, it can be desirable togenerate pulses for pulsed electric field ablation in synchronicity witha cardiac cycle. Synchronizing ablation energy delivery with the cardiaccycle may reduce the risk of induced arrhythmias such as atrial and/orventricular fibrillation. One method of synchronizing delivery of pulsescan be to pace of stimulate one or more cardiac cambers with periodicpacing signals with a predefined time period. For example, a cardiacstimulator may be used to deliver pacing pulses to one or more cardiacchambers such that the cardiac rhythm of a patient synchronizes with thepacing pulse. In some embodiments, pacing pulses can be delivered to thecardiac chamber(s) via an intracardiac catheter that is suitablypositioned in the chamber(s). The intracardiac catheter can include oneor more electrodes that are used to conduct the pacing signal into theheart. For example, the catheter can have a pair of electrodes (e.g., amost distal electrode and an electrode proximal to the distal electrode)that is used as a bipolar pair to deliver a pacing signal, with the twoelectrodes providing the forward and return current paths for the pacingsignal. The pacing pulse can cause the cardiac chamber to generate itselectrocardiogram (ECG) pulses in synchrony with the pacing pulses,thereby controlling the timing of the cardiac cycle.

Once the periodicity of the cardiac cycle is established and confirmed,e.g., by a physician, the delivery of high voltage ablation pulses canbe timed to start in synchrony with the pacing signals. For example, theablation pulses can be delivered with predetermined offsets from thepacing signals such that their delivery falls within the refractorywindow following the QRS waveform of the cardiac cycle. In someembodiments, the ablation pulses can be delivered to a cardiac chamberusing an ablation catheter configured for pulsed electric fieldablation.

While a cardiac chamber is being paced, however, localized electricalactivity (e.g., pre-ventricular contraction (PVC)) may trigger ectopiccardiac activity that generates an additional localized T-wave (e.g.,ectopic beat) that may overlap the next pacing pulse. Ablation energydelivered during these localized T-waves may have a high risk ofinducing fibrillation.

Accordingly, it can be desirable to detect such localized or ectopic ECGactivity that can occur between successive pacing pulses duringablation, such that the ablation system can ensure that ablation is notdelivered during those times. For example, an ablation device can beconfigured to be disconnected from a signal generator when ectopicactivity has been detected. By disconnecting or switching off theablation device (for example, with a suitable relay), the risk ofinducing a fibrillation event can be reduced.

Systems, devices, and methods described herein can be configured todetect ectopic signals and to control the operation of an ablationdevice based on such detection. For example, a system as describedherein may include a cardiac stimulator and pacing device used toelectrically pace the heart and ensure pacing capture to establishperiodicity and predictability of the cardiac cycle. The pacing devicemay be configured to measure electrical cardiac activity (e.g., anelectrocardiogram (ECG) signal) used to confirm pacing capture and/ordetect ectopic cardiac activity. For example, predetermined portions ofan ECG signal may be analyzed for an ectopic beat and synchronizationbetween a pacing pulse and cardiac cycle. A cardiac activity status maybe output to indicate the status of pacing capture and/or ectopiccardiac activity, and be used to control delivery of ablation energy totissue.

The system may further include a signal generator and a processorconfigured to apply one or more voltage pulse waveforms to a selectedset of electrodes of an ablation device to deliver energy to a region ofinterest (e.g., ablation energy for a set of tissue in a pulmonary veinostium). The pulse waveforms disclosed herein may aid in therapeutictreatment of a variety of cardiac arrhythmias (e.g., atrialfibrillation).

The cardiac stimulator may synchronize the generation of the pulsewaveform to a paced heartbeat in order to reduce unintended tissuedamage. For example, a time window within a refractory period of theperiodic cardiac cycle may be selected for voltage pulse waveformdelivery. Thus, voltage pulse waveforms may be delivered in therefractory period of the cardiac cycle so as to avoid disruption of thesinus rhythm of the heart. The pulse waveform may be generated based ona cardiac activity status indicating an absence of an ectopic beat andconfirmation of pacing capture. For example, the pulse waveform may begenerated in synchronization with a pacing signal of the heart to avoiddisruption of the sinus rhythm of the heart, and can be deliveredoutside of periods of detected ectopic activity. The pulse waveform canbe delivered to one or more electrodes of one or more catheters that areepicardially or endocardially placed around the heart, such that thoseelectrodes generate a pulsed electric field to ablate tissue. In someembodiments, the pulse waveform may include hierarchical waveforms toaid in tissue ablation and reduce damage to healthy tissue.

In some embodiments, an apparatus includes a memory and a processoroperatively coupled to the memory. The processor can be configured toreceive cardiac signal data captured by a set of electrodes; extract asliding window of the cardiac signal data; identify a peak frequencyover a subrange of frequencies associated with the extracted slidingwindow; detect ectopic activity based at least on a measure of the peakfrequency over the subrange of frequencies; and in response to detectingectopic activity, send an indication of ectopic activity to a signalgenerator configured to generate pulsed waveforms for cardiac ablationsuch that the signal generator is deactivated or switched off fromgenerating the pulsed waveforms.

In some embodiments, an apparatus includes a memory and a processoroperatively coupled to the memory. The processor can be configured toreceive cardiac signal data captured by a set of electrodes; receive anindication of delivery of a set of pacing pulses to the cardiac tissue;extract portions of the cardiac signal data following delivery of asubset of successive pacing pulses from the set of pacing pulses;calculate, for each extracted portion, a set of moments of a functionassociated with that extracted portion; confirm pacing capture of theset of pacing pulses based at least on the set of moments calculated foreach extracted portion; and in response to confirming pacing capture,send an indication of pacing capture to a signal generator configured togenerate pulsed waveforms for cardiac ablation such that the signalgenerator is activated for generating the pulsed waveforms. In someembodiments, the processor is further configured to: analyze local peakfrequencies of the cardiac signal data to detect ectopic activity; andin response to detecting ectopic activity, send an indication of ectopicactivity to the signal generator such that the signal generator isswitched off from generating the pulsed waveforms.

In some embodiments, a system includes a first controller configured togenerate a pulsed waveform and deliver the pulsed waveform in synchronywith a set of pacing pulses to an ablation device; and a secondcontroller operatively coupled to the first controller, the secondcontroller configured to: generate the set of pacing pulses and deliverthe set of pacing pulses to a pacing device; receive cardiac signal datacaptured by a set of electrodes; confirm pacing capture of the set ofpacing pulses based on the cardiac signal data; and in response toconfirming pacing capture, send an indication of pacing capture to thefirst controller to activate generation of the pulsed waveform. In someembodiments, the second controller is further configured to: monitor thecardiac signal data for ectopic activity; and when ectopic activity ispresent, send an indication of ectopic activity to the first controllerto switch off generation of the pulsed waveform.

In some embodiments, a method includes receiving cardiac signal datacaptured by a set of electrodes disposed near cardiac tissue; extractinga sliding window of the cardiac signal data; identifying a peakfrequency over a subrange of frequencies associated with the extractedsliding window; detecting ectopic activity based at least on a measureof the peak frequency over the subrange of frequencies; and in responseto detecting ectopic activity, sending an indication of ectopic activityto a signal generator configured to generate pulsed waveforms forcardiac ablation such that the signal generator is switch off fromgenerating the pulsed waveforms. The method can further includeconfirming pacing capture of the set of pacing pulses based on thecardiac signal data.

The term “electroporation” as used herein refers to the application ofan electric field to a cell membrane to change the permeability of thecell membrane to the extracellular environment. The term “reversibleelectroporation” as used herein refers to the application of an electricfield to a cell membrane to temporarily change the permeability of thecell membrane to the extracellular environment. For example, a cellundergoing reversible electroporation can observe the temporary and/orintermittent formation of one or more pores in its cell membrane thatclose up upon removal of the electric field. The term “irreversibleelectroporation” as used herein refers to the application of an electricfield to a cell membrane to permanently change the permeability of thecell membrane to the extracellular environment. For example, a cellundergoing irreversible electroporation can observe the formation of oneor more pores in its cell membrane that persist upon removal of theelectric field.

Pulse waveforms for electroporation energy delivery as disclosed hereinmay enhance the safety, efficiency and effectiveness of energy deliveryto tissue by reducing the electric field threshold associated withirreversible electroporation, thus yielding more effective ablativelesions with a reduction in total energy delivered. In some embodiments,the voltage pulse waveforms disclosed herein may be hierarchical andhave a nested structure. For example, the pulse waveform may includehierarchical groupings of pulses having associated timescales. In someembodiments, the methods, systems, and devices disclosed herein maycomprise one or more of the methods, systems, and devices described inInternational Application Serial No. PCT/US2019/014226, filed on Jan.18, 2019, published as International Publication No. WO/2019/143960 onJul. 25, 2019, and titled “SYSTEMS, DEVICES AND METHODS FOR FOCALABLATION,” the contents of which are hereby incorporated by reference inits entirety.

Systems

Disclosed herein are systems and devices configured for monitoringectopic cardiac activity in connection with tissue ablation via theselective and rapid application of voltage pulse waveforms resulting inirreversible electroporation. Generally, a system for ablating tissuedescribed here may include a cardiac stimulator for generating a pacingsignal delivered by a pacing device to the heart. The system furthermeasures electrical cardiac activity for identification of ectopic beatsand/or to confirm pacing capture of the heart. The detected pacingsignal and/or detected cardiac activity can be used to control deliveryof a pulse waveform generated by a signal generator to an ablationdevice having one or more electrodes. As described herein, the systemsand devices may be deployed epicardially and/or endocardially to treatheart conditions such as, for example, atrial fibrillation. Voltages maybe applied to a selected subset of the electrodes, with independentsubset selections for anode and cathode electrode selections.

Generally, the systems and devices described herein include one or moredevices (e.g., catheters) configured to ablate tissue in a left atrialchamber of a heart. FIG. 1 illustrates a system (100) configured todeliver voltage pulse waveforms. The system (100) may include anapparatus (120) including one or more processor(s) or controller(s)(124) and a memory (126). The processor(s) (124) can function as, beintegrated into, and/or control a signal generator (122) and/or acardiac stimulator (128).

Each of the one or more processor(s) (124) may be any suitableprocessing device configured to run and/or execute a set of instructionsor code. The processor may be, for example, a general purpose processor,a Field Programmable Gate Array (FPGA), an Application SpecificIntegrated Circuit (ASIC), a Digital Signal Processor (DSP), and/or thelike. The processor may be configured to run and/or execute applicationprocesses and/or other modules, processes and/or functions associatedwith the system and/or a network associated therewith (not shown). Theunderlying device technologies may be provided in a variety of componenttypes, e.g., metal-oxide semiconductor field-effect transistor (MOSFET)technologies like complementary metal-oxide semiconductor (CMOS),bipolar technologies like emitter-coupled logic (ECL), polymertechnologies (e.g., silicon-conjugated polymer and metal-conjugatedpolymer-metal structures), mixed analog and digital, and/or the like.

The memory (126) may include a database (not shown) and may be, forexample, a random access memory (RAM), a memory buffer, a hard drive, anerasable programmable read-only memory (EPROM), an electrically erasableread-only memory (EEPROM), a read-only memory (ROM), Flash memory, etc.The memory (126) may store instructions to cause the processor (124) toexecute modules, processes and/or functions associated with the system(100), such as pulse waveform generation and/or cardiac pacing.

The apparatus (120) may be coupled to an ablation device (110) and/or apacing device (130). When coupled to the ablation device (110) andpacing device (130), one or more components of the apparatus (120)(e.g., a processor (124) functioning as a signal generator (122) and/orcardiac stimulator (128)) can be in electrical communication with theablation device (110) and/or pacing device (130) to control delivery ofpacing signals, ablation signals, etc. via the ablation device (110) andpacing device (130) and/or to receive data (e.g., sensed signals) fromthe ablation device (110) and pacing device (130). If apparatus (120)includes multiple processors (124), one or more of the processor(s)(124) can communicate with one another to control pacing and/orablation. The apparatus (120) can also include an input/output device(127) that enables the apparatus (120) to interface with other devices(e.g., ablation device (110) and/or pacing device (130)) and/or a user.For example, the apparatus (120) can include a user interface, e.g., adisplay, an audio device, etc. that enables presentation of outputs to auser and/or receipt of input from the user.

The signal generator (122) may be configured to generate ablation pulsewaveforms for irreversible electroporation of tissue, such as, forexample, pulmonary vein ostia. For example, the signal generator (122)may be a voltage pulse waveform generator and deliver a pulse waveformto the ablation device (110). The processor (124) may incorporate datareceived from memory (126), cardiac stimulator (128), and pacing device(130) to determine the parameters (e.g., timing, amplitude, width, dutycycle, etc.) of the pulse waveform to be generated by the signalgenerator (122). The memory (126) may further store instructions tocause the signal generator (122) to execute modules, processes and/orfunctions associated with the system (100), such as ectopic cardiacactivity detection, pulse waveform generation, and/or cardiac pacingsynchronization. For example, the memory (126) may be configured tostore one or more of cardiac activity data, pulse waveform, and heartpacing data.

The pacing device (130) disposed in the patient may be configured toreceive a heart pacing signal generated by the cardiac stimulator (128)of the apparatus (120) for cardiac stimulation. An indication of thepacing signal may be transmitted by the cardiac stimulator (128) to thesignal generator (122). Based on the pacing signal, an indication of avoltage pulse waveform may be selected, computed, and/or otherwiseidentified by the processor (124) and generated by the signal generator(122). In some embodiments, the signal generator (122) is configured togenerate the pulse waveform based on a cardiac activity status where thepulse waveform is in synchronization with the indication of the pacingsignal (e.g., within a common refractory window). For example, in someembodiments, the common refractory window may start substantiallyimmediately following a ventricular pacing signal (or after a very smalldelay) and last for a duration of approximately 250 milliseconds (ms) orless thereafter. In such embodiments, an entire pulse waveform may bedelivered within this duration.

In some embodiments, one or more intracardiac electrodes, e.g., of thepacing device (130) and/or ablation device (110), can be configured tosense signals within the heart and deliver those signals to one or moreof the processor(s) 124. The one or more processor(s) 124 can analyzethe sensed signals for ectopic activity and control operation of thesignal generator (122) based on such analysis, as further describedbelow.

The system (100) may be in communication with other devices (not shown)via, for example, one or more networks, each of which may be any type ofnetwork. A wireless network may refer to any type of digital networkthat is not connected by cables of any kind. However, a wireless networkmay connect to a wireline network in order to interface with theInternet, other carrier voice and data networks, business networks, andpersonal networks. A wireline network is typically carried over coppertwisted pair, coaxial cable or fiber optic cables. There are manydifferent types of wireline networks including, wide area networks(WAN), metropolitan area networks (MAN), local area networks (LAN),campus area networks (CAN), global area networks (GAN), like theInternet, and virtual private networks (VPN). Hereinafter, networkrefers to any combination of combined wireless, wireline, public andprivate data networks that are typically interconnected through theInternet, to provide a unified networking and information accesssolution. The system (100) may further comprise one or more outputdevices such as a display, audio device, touchscreen, combinationsthereof, and the like.

FIG. 2 is a schematic illustration of a heart (200), e.g., as seen froman anterior side (e.g., front of a subject) including an ablation device(220) and a pacing device (210) disposed therein, according toembodiments described herein. The pacing device (210) may be configuredto measure cardiac activity and/or deliver pacing signal to the heart(200), and the ablation device (220) may be configured to receive and/ordeliver a pulse waveform to cardiac tissue. As illustrated, in theanterior cross-section of the heart (200) depicted in FIG. 2, the dottedlines (201) schematically approximate the boundaries of the four heartchambers including the right ventricle RV (202) and left atrium LA(204). Pacing device (210) may be introduced into the right ventricle(202) and positioned such that it can stimulate the right ventricle(202) and obtain pacing capture. The pacing device (210) may comprisefirst electrode (212), second electrode (214), third electrode (216),and fourth electrode (218). The first electrode (212) and the secondelectrode (214) may be configured as a bipolar pair of pacing electrodesto pace the right ventricle (202). The pacing electrodes (212, 214) maybe coupled to a cardiac stimulator (e.g., cardiac stimulator (128)). Thethird electrode (216) and the fourth electrode (218) may be configuredas sensor elements to measure intracardiac activity (e.g., ECG signal)of the heart (200). While the pacing device (210) is described as beingpositioned in the right ventricle (202), it can be appreciated that thepacing device (210) can be positioned in other suitable sites. Forexample, the pacing device (210) can be placed in the coronary sinus,and a suitable electrode pair (e.g., electrodes (212, 214)) may be usedto pace the ventricle.

The ablation device (220) may be introduced into an endocardial space ofthe left atrium (204) through an atrial septum via a trans-septalpuncture. The distal portion of the ablation device (220) may include aset of electrodes (222, 224) configured to deliver ablation energy(e.g., pulse electric field energy) to tissue. In some embodiments, theelectrodes (222, 224) of the ablation device (220) may be a set ofindependently addressable electrodes. Each electrode may include aninsulated electrical lead configured to sustain a voltage potential ofat least about 700 V without dielectric breakdown of its correspondinginsulation. In some embodiments, the insulation on each of theelectrical leads may sustain an electrical potential difference ofbetween about 200 V to about 2,500 V across its thickness withoutdielectric breakdown. In some embodiments, the set of electrodes mayinclude a plurality of electrodes. The plurality of electrodes may begrouped into one or more anode-cathode subsets such as, for example, asubset including one anode and one cathode, a subset including twoanodes and two cathodes, a subset including two anodes and one cathode,a subset including one anode and two cathodes, a subset including threeanodes and one cathode, a subset including three anodes and twocathodes, and/or the like. While two electrodes (222, 224) are depicted,it can be appreciated that ablation device (220) can include one or moreadditional electrodes, where one or more sets of electrodes can beconfigured with opposite polarities to deliver pulsed electric fields toablate tissue.

The operation of systems and devices for detection of pacing signalsand/or ectopic activity can be understood with reference to FIGS. 3A and3B, which schematically illustrate a time series of periodic pacingpulses with cardiac activity, according to embodiments described herein.

FIG. 3A is a schematic illustration of a time sequence of anelectrocardiogram (300) and cardiac pacing signal (310). The pacingsignal (310) may comprise a set of periodic pacing pulses (312). Forexample, the pacing pulse (312) may comprise a rectangular pulse havinga width of between about 1 ms and about 5 ms. In some embodiments, thepacing pulses (312) may be delivered using any of the pacing devices(e.g., pacing devices (130, 210)) described herein. For example, thepacing pulse (312) may be delivered via pacing electrodes (212, 214) ofpacing catheter (210). In response to the pacing pulses (312), thecardiac cycle of the heart may synchronize with the pacing pulses (312).For example, the QRS waveforms (302) in FIG. 3A are synchronized withrespective pacing pulses (312). The T-wave (304) that follows the QRSwaveform (302) corresponds to the start of repolarization occurring inthe cardiac myocytes. As such, delivery of an ablation pulse waveformafter the T-wave begins may cause complications (e.g., atrial and/orventricular fibrillation) and therefore be avoided. The time period(330) that starts from the onset of the pacing pulse (312) and endsbefore the T-wave (304) represents a safe time window during which anablation pulsed electric field can be delivered to the heart. In someembodiments, ablation pulse waveforms are delivered within a refractoryperiod (320) of the cardiac cycle following the pacing pulse (312). Insome embodiments, more than one cardiac chamber may be paced (e.g.,simultaneous pacing of an atrium and a ventricle) to establish a commonrefractory period for more than one cardiac chamber. In suchembodiments, the pacing pulse (312) can be delivered during a commonrefractory period or overlap in the refractory period associated witheach cardiac chamber.

FIG. 3B is a schematic illustration of a time sequence of anelectrocardiogram (340) and cardiac pacing signal (350). Similar to theperiodic pacing pulses (312) shown in FIG. 3A, each pacing pulse (352)may comprise a rectangular pulse having a width of between about 1 msand about 5 ms, and may be delivered using any of the pacing devices(e.g., pacing devices (130, 210)) described herein. For example, thepacing pulse (352) may be delivered via pacing electrodes (212, 214) ofpacing catheter (210). In response to the pacing pulses (352), thenatural pacing function of the heart may synchronize with the QRSwaveforms (342). The T-wave (344) that follows the QRS waveform (342)corresponds to the start of repolarization in the cardiac myocytes.Without ectopic activity, the time period (370) that starts from theonset of the pacing pulse (352) and ends before the T-wave (344)represents a safe time window during which an ablation pulsed electricfield can be delivered to the heart. The electrocardiogram (340)includes a refractory period (360) during which ablation can bedelivered. With ectopic activity, e.g., as represented by an ectopicpulse (380) in the electrocardiogram (340), delivery of pulsed electricfield ablation during the time period (370) may induce fibrillation. Asdepicted in FIG. 3B, an ectopic pulse or complex (380) can precede theQRS waveform (342) synchronized with the pacing pulse (352). The ectopicpulse (380) may generate an ectopic T-wave (382) that precedes theT-wave (344) of the QRS waveform (342). If a pulse waveform is deliveredduring the period (328) following the ectopic pulse (380), the pulsewaveform may overlap the ectopic T-wave (382) and thereby causecomplications, e.g., by inducing fibrillation. Accordingly, it can bedesirable to detect the occurrence of an ectopic complex such as ectopicpulse (380) during an ablation procedure (e.g., in real-time), and upondetection, interrupt delivery of pulsed electric field ablation pulses.As described in more detail herein, systems, devices, and methodsdescribed herein can enable ectopic beats to be detected in real-time(e.g., during a pacing and/or ablation process) and delivery of ablationenergy to tissue to be controlled (e.g., interrupting delivery of pulsewaveform pulses) in response thereto. For example, such systems,devices, and methods can be configured for automated detection ofectopic ECG activity such that, if an ectopic beat is detected,subsequent ablation delivery can be terminated, e.g., until a user hasrepositioned devices, adjusted pacing parameters, or made other clinicaladjustments to obtain a ECG waveform in synchrony with pacing pulsesthat does not include ectopic activity.

FIG. 4 schematically depicts an example apparatus (903) for generatingpulsed electric field energy for tissue ablation. The apparatus (903)can include components that are structurally and/or functionally similarto those of the apparatus (120), described above with reference toFIG. 1. In an embodiment, the apparatus (903) includes at least twocontrollers or processors (907, 908). The controller (907) can beconfigured to generate a waveform for pulsed electric field ablation viaan ablation output (911) that connects to an energy delivery device suchas, for example, an ablation catheter (e.g., ablation device (110)).

The controller (908) can be configured to generate a pacing stimulus andsend that pacing stimulus to an intracardiac pacing catheter or similarmedical device (e.g., pacing device (130)) via pacing output (920). Thecontroller (908) can further send an indication (915) of the pacingstimulus to the controller (907), such that the delivery of the pulsedelectric field energy can be synchronized with the cardiac pacing. Thecontrollers (907, 908) can be operatively coupled to one another, e.g.,by a communication bus (917). By synchronizing the delivery of thepulsed electric field ablation energy to the pacing stimulus, theapparatus (903) can ensure that pulsed electric field energy is deliveryto sensitive anatomical structures (e.g., a cardiac chamber) during arefractory period, as described above, thereby avoiding the risk ofinducing an arrhythmia such as a fibrillation event.

In some instances, an ectopic beat can arise by autonomous generationfrom a cardiac chamber. As described above, pulsed electric fieldablation delivered during periods of ectopic activity can increase therisk of inducing an arrhythmia. Accordingly, it can be desirable todetect such ectopic activity. To detect such activity, cardiac signals(e.g., ECG recordings) from an intracardiac electrode pair can be sentas sensing signals (922) to the controller (908). The controller (908)can be configured to analyze the cardiac signals for ectopic beats. Whenthe controller (908) detects an ectopic beat, the controller (908) canbe configured to communicate with the controller (907) responsible forgenerating the ablation waveform, e.g., via communication bus (917), tohalt the delivery of the pulsed electric field energy. For example, thecontroller (908) can send a signal to halt or interrupt ablation to thecontroller (907) in response to detecting ectopic activity.

In some embodiments, the apparatus (903) can be configured to confirmpacing capture prior to delivery of pulsed electric field energy. Forexample, the apparatus (903) via controller (908) can analyze the sensedcardiac signals (922) and communicate with controller (907) to deliverablation upon confirmation of pacing capture. In some embodiments, theapparatus (903) can be equipped with a user interface for confirmingpacing capture, e.g., via a manual input (927) by a user. For example,the apparatus (903) can include a display that displays the pacingsignal and cardiac signal to allow a user to confirm pacing capture andindicate such confirmation to the apparatus (903) (e.g., by pushing abutton on the user interface). In some embodiments, the apparatus (903)can analyze the sensed cardiac activity, and if such is found to not bein synchrony with the pacing stimulus, not perform ablation deliveryand/or inform a user that pacing capture is absent (e.g., via userinterface or a message). The user and/or apparatus (903) can then modifythe pacing conditions, e.g., attempt pacing capture at a different rate,or move the pacing catheter to a location or position with betteranatomical engagement.

FIG. 5 schematically depicts an example flow of a signal (e.g., an ECGsignal) through one or more components of a controller, such as, forexample, controller (908) depicted in FIG. 4, in more detail. Asdepicted, an incoming signal (1003) (e.g., raw analog cardiac activitysignal captured using intracardiac electrodes) can be received at anamplifier (1007). Amplifier (1007) may be configured to amplify thesignal (1003) for digitization by an analog-to-digital converter (ADC)(1009). The ADC (1009) can output the processed cardiac data as a streamof digitized data. The digitized data may be stored or buffered ascardiac activity data in memory (1011). The processor (1013) may analyzeand/or process the buffered cardiac data in segments of predeterminedsize (e.g., windowed data) for ectopic cardiac activity.

In some embodiments, the analysis can be based on comparing data to oneor more threshold values, e.g., predetermined and preprogrammed into theprocessor (1013) and/or provided by a user via a user input (1017) to auser interface (e.g., a touchscreen monitor or other type of monitor,etc.). Based on the analysis, the processor (1013) may be configured tooutput a cardiac activity status to a controller for generating anablation waveform or pulse generator controller (e.g., the signalgenerator (122) or the controller (907)).

The signal (1015) may indicate one or more of pacing capture status(e.g., ECG signal in/out of synchrony with a pacing pulse) and ectopiccardiac activity status. For example, if pacing capture is not detected,the processor (1013) can send a corresponding status signal (1015)indicating a lack of pacing capture to a pulse generator controller. Theprocessor (1013) and/or the pulse generator controller can then alert auser, e.g., through a user interface, that pacing capture is not presentand ablation cannot be performed. The user can then take appropriateaction such as, for example, halting an ablation procedure and/orreconfiguring the system. For example, the user may reposition one ormore of an ablation device (e.g., ablation device (110)) and/or pacingdevice (e.g., pacing device (130)), and/or adjust other systemparameters. If pacing capture is confirmed by the processor (1013), adifferent signal (1015) indicating readiness for ablation can be sent tothe pulse generator controller, whereupon the pulse generator controllermay be configured to initiate ablation when requested by a user. In someembodiments, systems and devices described herein may measure cardiacactivity before, during, and after ablation energy delivery.

Additionally or alternatively, the processor (1013) can detect ectopicbeats. For example, if pacing capture is confirmed but an ectopic beatis detected, the processor (1013) can be configured to send a signal(1015) to the pulse generator controller such that the pulse generatorcontroller does not generate a pulse waveform for ablation. Theprocessor (1013) and/or pulse generator controller can inform a user tothe presence of ectopic beats and that ablation cannot be performed,e.g., via a user interface. The processor (1013) can also continue tomonitor the sensed ECG signal for ectopic beats that may occur duringablation. If such ectopic beats are detected, the processor (1013) cansend a signal (1015) to the pulse generator controller indicating thatablation should be paused or interrupted. The pulse generate controller,in response to receiving the signal (1015) can then half furtherablation delivery, e.g., until the user adjusts the system and/or noectopic beat activity is detected.

Methods

Also described here are methods for detecting ectopic cardiac activityduring a tissue ablation process performed in a heart chamber using thesystems and devices described above. The heart chamber may be the leftatrial chamber and include its associated pulmonary veins. Generally,the methods described here include introducing and disposing a pacingdevice (e.g., pacing device (130), pacing device (210)) in contact withone or more heart chambers. The pacing device may measure cardiacactivity and deliver a pacing signal to the heart using a cardiacstimulator or other processor (e.g., cardiac stimulator (128),controller (908), processor (1013)). The measured signals may beprocessed and analyzed to detect pacing capture and/or ectopic cardiacactivity that may interfere with tissue ablation, e.g., by suchprocessor and controllers as described herein. An ablation device (e.g.,ablation device (110), ablation device (220)) may be introduced anddisposed in contact with one or more pulmonary vein ostial or antralregions. A pulse waveform may be delivered by one or more electrodes(e.g., electrodes (112), electrodes (222, 224)) of the ablation deviceto ablate tissue. In some embodiments, detection of autonomouslygenerated ectopic cardiac activity may drive prompt interruption ofablation energy delivery, thereby reducing the risk of inducing anarrhythmia (e.g., fibrillation). Furthermore, a cardiac pacing signal(e.g., delivered by a pacing device (e.g., pacing device (130), pacingdevice (210)) may synchronize the delivered pulse waveforms with thecardiac cycle. By synchronizing the delivery of ablation energy to apacing stimulus (e.g., during a refractory period), the risk of inducingan arrhythmia such as fibrillation may be further reduced.

Additionally or alternatively, the pulse waveforms may include aplurality of levels of a hierarchy to reduce total energy delivery,e.g., as described in International Application Serial No.PCT/US2019/031135, filed on May 7, 2019, and titled “SYSTEMS,APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE,” thecontents of which are hereby incorporated by reference in its entirety.The tissue ablation thus performed may be delivered in the absence ofectopic cardiac activity and in synchrony with paced heartbeats toreduce the risk of atrial and/or ventricular fibrillation and damage tohealthy tissue. It should be appreciated that any of the ablationdevices described herein (e.g., ablation device (110), ablation device(220)) may be used to ablate tissue using the methods discussed below asappropriate.

In some embodiments, the ablation devices described herein (e.g.,ablation device (110), ablation device (220)) may be used for epicardialand/or endocardial ablation. Examples of suitable ablation catheters aredescribed in International Application Serial No. PCT/US2019/014226.

FIG. 6 is an example method (400) of tissue ablation. In someembodiments, the voltage pulse waveforms described herein may be appliedduring a refractory period of the cardiac cycle so as to avoiddisruption of the sinus rhythm of the heart. The method (400) includesintroduction of a pacing device (e.g., pacing device (130, 210)) into anendocardial space, e.g., of a right ventricle, at (402). The pacingdevice may be advanced to be disposed in contact with the cardiactissue, at (404). For example, sensor electrodes configured for cardiacactivity measurement (e.g., ECG signals) and pacing electrodesconfigured for delivering pacing signals may be disposed in contact withan inner surface of the right ventricle. An ablation device (e.g.,ablation device (110, 220)) may be introduced into an endocardial space,e.g., of a left atrium, at (406). The ablation device may be advanced tobe disposed in contact with a pulmonary vein ostium, at (408). In someembodiments, a pacing signal may be generated by a cardiac stimulator(e.g., cardiac stimulator (128)) for cardiac stimulation of the heart,at (410). The pacing signal may then be applied to the heart, at (412),using the pacing electrodes of the pacing device. For example, the heartmay be electrically paced with the pacing signal to ensure pacingcapture to establish periodicity and predictability of the cardiaccycle. One or more of atrial and ventricular pacing may be applied.Examples of applied pacing signals relative to patient cardiac activityare described in more detail herein with respect to FIGS. 3A and 3B. Oneor more electrodes of the pacing device and/or ablation device mayfurther measure cardiac activity (e.g., ECG signal) corresponding toelectrical cardiac activity of the heart, at (414). In some embodiments,cardiac activity may be measured before, during, and/or after cardiacstimulation and tissue ablation.

An apparatus (e.g., apparatus (120, 903)) can process and/or analyze thecardiac signal sensed by the one or more electrodes. Based on analysisof the cardiac data, a status signal may be generated, at (416). Thestatus signal may indicate a status of one or more of pacing captureand/or ectopic cardiac activity. For example, FIGS. 7, 9, and 10 providemore detailed examples of detecting ectopic cardiac activity. The statussignal may be output to one or more of a signal generator (e.g., signalgenerator (122)) or any processor associated with an ablation device(110, 220) and/or output to a user interface, at (418). Based on thestatus signal, the signal generator may or may not generate a pulsewaveform, at (420), e.g., based on predetermined criteria as describedherein. For example, the pulse waveform may be generated insynchronization with the pacing signal (e.g., during a refractoryperiod) when the status signal indicates one or more of a lack ofectopic cardiac activity (e.g., ectopic beat) in the cardiac data andconfirmation of pacing capture (e.g., synchronization between the pacingsignal and the cardiac cycle). For example, when pacing capture isobserved over several heartbeats without ectopic cardiac activity, thenthe signal generator may generate a pulse waveform upon user (e.g.,operator) activation. Conversely, the signal generator may be configuredto inhibit pulse waveform generation and/or output an alert to the userwhen the cardiac activity status indicates one or more of ectopiccardiac activity (e.g., ectopic beat) in the cardiac data and/or anabsence of pacing capture.

In some embodiments, pacing capture may be automatically confirmed byapparatuses described herein (e.g., apparatus (120, 903)) based on thereceived cardiac data. Additionally or alternatively, pacing capture maybe confirmed by a user, e.g., after viewing an output of the pacingsignal and cardiac signal data. For example, the user may confirm pacingcapture using a user interface (e.g., an input/output device such as atouch screen monitor or other type of monitor) based on a cardiacactivity output on a display. If the signal generator and/or processor,or the user viewing the displayed cardiac output, determines that thereis one or more of ectopic cardiac activity and an absence of pacingcapture, pulse waveform generation may be prohibited and the user may beprompted to adjust system parameters by, for example, repositioning thepacing device to improve tissue engagement and/or modify pacing signalparameters (e.g., pulse width, pulse amplitude, pulse frequency, etc.).

The generated pulse waveform may be delivered to tissue, at (422). Insome embodiments, a voltage pulse waveform may be applied in a commonrefractory time period associated with atrial and ventricular pacingsignals. Depending on the cardiac data that is captured and/or otherparameters associated ablation delivery, the pulse waveform may begenerated with a time offset with respect to the indication of thepacing signal. For example, the refractory time period may be offsetfrom the pacing signal by predetermined time period, and the ablationdevice can be configured to deliver the pulses during the refractorytime period that is offset from the pacing signal. In some embodiment,the voltage pulse waveform(s) may be applied over a series of heartbeatsover corresponding refractory time periods (e.g., common refractoryperiods).

In some embodiments, the pulse waveform may be delivered to pulmonaryvein ostium of a heart of a patient via one or more splines of a set ofsplines of an ablation device (e.g., ablation device (110, 220). Inother embodiments, voltage pulse waveforms as described herein may beselectively delivered to electrode subsets such as anode-cathode subsetsfor ablation and isolation of the pulmonary vein. For example, a firstelectrode of a group of electrodes may be configured as an anode and asecond electrode of the group of electrodes may be configured as acathode. These steps may be repeated for a desired number of pulmonaryvein ostial or antral regions to have been ablated (e.g., 1, 2, 3, or 4ostia). Suitable examples of ablation devices and methods are describedin International Application No. PCT/US2019/014226.

FIG. 7 is an example method (500) for detecting ectopic cardiacactivity. In some embodiments, one or more steps of the method (500) maybe performed by any one of the apparatuses described herein (e.g.,apparatus (120, 903)), or any suitable processor associated with devicesand methods described herein. The method (500) includes receiving acardiac activity signal corresponding to electrical cardiac activity(e.g., ECG waveforms) of the heart, at (502). For example, the cardiacactivity signal may include analog data received continuously from a setof electrodes (e.g., electrodes (216, 218)) of a pacing device (e.g.,pacing device (210)) in contact with a chamber of a heart (e.g., theright ventricle). In some embodiments, a processor (e.g., controller(908), processor (1013)) or other processor associated with an ablationdevice may receive the cardiac activity signal and perform ectopiccardiac activity detection. The raw cardiac activity signal may bereceived and processed, at (504), to generate processed cardiac activitydata. For example, signal processing may include signal conditioning(e.g., filtering), amplification, and digitization (e.g., using ananalog-to-digital converter (ADC)) to generate processed cardiacactivity data. For example, the cardiac activity signal may be sampledat a frequency in the range of about 1 kHz or sampling time intervals ofabout 1 ms and stored at a predetermined resolution (e.g., discrete timeseries of 16-bit signed integer data). A sampling time interval of 1 mscorresponds to a Nyquist frequency of 500 Hz. The processed cardiacactivity data is stored in memory, at (506), such as a buffer. In someembodiments, the buffer clears the stored cardiac data based on areceived pacing signal. For example, the buffer deletes the previouslystored cardiac data upon receiving the next pacing pulse. In someembodiments, the pacing signal may include a predetermined pacingfrequency.

The processed cardiac activity data may be analyzed for one or more ofectopic cardiac activity and pacing capture, at (508). For example, theprocessed cardiac activity data can be analyzed by extracting slidingwindows of the data, and each sliding window can be evaluated forectopic cardiac activity, e.g., using discrete Fourier transformmethods. Specific implementations of such analysis are further describedwith reference to FIGS. 9 and 10. Optionally, in some embodiments, theprocessed cardiac activity data can be analyzed to confirm pacingcapture, at (512).

In some embodiments, ectopic cardiac activity detection, at (510), maybe performed in parallel with pacing capture detection, at (512). Inother embodiments, pacing capture detection, at (512), can be performedprior to performing ectopic cardiac activity detection, at (510).

A status signal may be generated, at (514), based on the results of thedetected ectopic cardiac activity and/or pacing capture. In someembodiments, the status signal may be output to one or more componentsof an ablation apparatus (e.g., apparatus (120)), including, forexample, a signal or pulse generator (e.g., signal generator (122))and/or another compute device. For example, a user interface (e.g., auser interface such as a display, including in an apparatus (120)) of atissue ablation system may be configured to display an indicationconfirming pacing capture (e.g., “Pacing Capture Confirmed”) and displayan “Ablation” icon configured to allow a user to initiate delivery ofablation energy to tissue. In some embodiments, the cardiac activitystatus need not be output to a user if pacing capture is confirmed andno ectopic beat is detected. Rather, an indication (e.g., an audioand/or visual alarm) can be made when either pacing capture cannot beconfirmed or when an ectopic beat is detected.

FIGS. 9 and 10 are flow charts depicting example methods of detectingectopic cardiac activity and/or confirming pacing capture. One or moresteps of the methods may be performed by any one of the apparatusesdescribed herein (120, 903), or any suitable processor associated withdevices and methods described herein. As depicted in FIG. 9, a method ofdetecting ectopic cardiac activity includes receiving an ECG input, at(702). The ECG input can be, for example, ECG signal data received froma set of electrodes of a pacing device (e.g., electrodes (216, 218) ofpacing device (210)). The ECG signal can be an analog signal. The ECGinput can be processed, at (704), e.g., by conditioning (e.g.,filtering) and/or amplifying the signal. The ECG signal can be convertedfrom analog to digital, e.g., using an ADC, at (706). In someembodiments, the data can be sampled at a frequency to achievesufficient resolution, e.g., at a frequency of about 1 kHz or samplingtime intervals of about 1 ms, and stored as bit-based integer data(e.g., 16-bit signed integer data, 32-bit signed integer data, etc.).The digitized or sampled data can be stored in a memory (e.g., memory(126, 1011)), at (708). For example, the data can be buffered startingwith each pacing signal such that each set of buffered data isassociated with a single heart beat or cardiac cycle. The pacing signaldata can be provided, e.g., by a pacing device (e.g., pacing device(130, 210)) and/or processor associated with a pacing device (e.g.,processor (124, 908, 1013)), at (737). When a later set of dataassociated with a second pacing signal is received, the existing buffercan be cleared and this new data associated with the second pacingsignal can be stored in the buffer.

At (710), the buffered data may be analyzed by extracting slidingwindows of predetermined length. For example, beginning at a timeinterval equal to the pacing pulse width after the leading edge of thepacing pulse, the buffered data is extracted in sliding windows of apredetermined length (e.g., a window of 220 data points), whichcorresponds to a frequency resolution of approximately 4.54 Hz. Thesliding window can start after the pacing pulse (i.e., after a timeinterval equal to the pulse width), and be advanced in discrete steps,e.g., with a step size equal to a preset number of sampling timeintervals such as 10 sampling time intervals. The number of slidingwindows extracted from the buffered data per cardiac cycle may depend onone or more parameters, such as, for example, a length between pacingpulses, window length, and/or step size, each of which can be apredetermined parameter.

A discrete Fourier Transform (e.g., Fast Fourier Transform) may beperformed for each sliding window, at (712). The result of the FourierTransform (e.g., amplitude) may be filtered (e.g., by a smoothingfilter) to output a function ƒ corresponding to a local average over aset of neighboring values around each data point, at (714). Local peaksin function ƒ may be identified over a subrange of the data of eachsliding window. For example, if a sliding window had a length of 220data points, a subrange ranging from about 12 to about 100 (12^(th) datapoint to 100^(th) data point) can be used, which corresponds to afrequency band from about 54 Hz to about 454 Hz. While these specificsliding window lengths and frequency bands are provided as examples, itcan be appreciated that other sliding window lengths and frequency bandscan be used, e.g., depending on desired parameters, processingcapability, etc. Analysis of peaks within the frequency band can be usedto determine whether ectopic cardiac activity is present, at (720).

The processed ECG data within each sliding window can be used to detectectopic cardiac activity. In an embodiment, an ectopic beat may bedetected based on a comparison between a ratio of a peak value (a_(p))of ƒ over the predetermined interval (or subrange or frequency band) tothe maximum value (a_(max)) of ƒ up to the Nyquist frequency to apredetermined threshold t. In some embodiments, an ectopic beat may bedetected in the sliding window when the ratio a_(p)/a_(max) is greaterthan t. Because ectopic beats increase the amount of certain frequenciesin ECG signals, detection can be accomplished by identifying instanceswhere a greater than normal amount of a frequency is present in thesampled cardiac data. In some embodiments, t may be between about 0.01and about 0.25, between about 0.01 and about 0.2, between about 0.01 andabout 0.15, including all sub-values and ranges in-between. In someembodiments, the user may input t into a user interface of a tissueablation system, at (716). The threshold t can represent a sensitivityof the system, i.e., a system with a lower threshold t would havegreater sensitivity than a system with higher threshold t.

When an ectopic beat is not detected in a particular sliding window(720: NO), the process continues onto the next sliding window. When anectopic beat is detected (720: YES), then a status signal can begenerated, at (724), e.g., that notifies a compute device and/or a userof the ectopic activity, as described above with reference to (514) inFIG. 7.

In some embodiments, received ECG data can be used to confirm pacingcapture. For example, as depicted in FIG. 10, an example method fordetecting ectopic beats and confirming pacing capture is depicted.Similar to the method depicted in FIG. 9, an ECG input can be received,at (802). At (804), the ECG input can be processed, e.g., byconditioning (e.g., filtering) and/or amplifying the signal. At (806),the ECG signal can be converted from analog to digital, e.g., using anADC. At (808), the digitized data can be stored in a memory (e.g.,memory (126)). For example, the digitized data can be buffered in thememory starting with each pacing signal such that each set of buffereddata is associated with a single heart beat or cardiac cycle.

At (810), the buffered data may be analyzed by extracting slidingwindows of the data, each sliding window having a predetermined lengthand being advanced in discrete steps through the buffered data.Detection of ectopic beats, e.g., via a discrete Fourier Transform ofthe data, at (812), filtering and analysis of the data, at (814), anddetection of peaks in the Fourier Transform data that is greater than apreset threshold, at (820), can be similar to that described in FIG. 9.In some embodiments, such detection can be based on a user input (816).

With ECG data being available, pacing capture can also be confirmed, at(822). To confirm pacing capture, a subset of sampled data can beextracted from the ECG data at the start of the pacing signal, asindicated by (837). For example, ECG data associated with apredetermined time interval T (e.g., a pacing pulse duration) startingfrom onset of a pacing pulse can be extracted. For example, the timeperiod may have a length of between about 5 ms and about 50 ms.Accordingly, the subset of sampled data can, for example, include thefirst ten to fifty data points, depending on the sampling frequency andtime interval T A function g(t) may be defined by the subset of sampleddata over the time interval T. In some embodiments, g(t) may representan ECG signal scaled with respect to a maximum magnitude of the ECGsignal over the time interval T. A set of moments (e.g., M₀, M₁, . . . ,M_(n)) of this function over the time interval T may be calculated, andcan be tracked over a predetermined number of successive pacing periods(e.g., 1, 2, 3, 4, 5 successive pacing periods). The set of moments ofthe function can include, for example, the first three moments, whichcan be computed in discretized form as average values, or as othersuitable integral representations (e.g., using the trapezoidal rule,Simpson's rule, or other integral measures) of g(t), tg(t), and t²g(t)over the time interval T.

With the calculated moments, an average value A_(n) of the nth momentover a set of i successive periods may be given by: A_(n)=(M_(n) ¹+M_(n)²+M_(n) ³+ . . . +M_(n) ^(i))/i. Accordingly, for the first threemoments over 5 successive pacing periods, the average values will be:A ₀=(M ₀ ¹ +M ₀ ² + . . . M ₀ ⁵)/5A ₁=(M ₁ ¹ +M ₁ ² + . . . M ₁ ⁵)/5A ₂=(M ₂ ¹ +M ₂ ² + . . . M ₂ ⁵)/5

A normalized difference between the average moment value A_(n) and themoment value for the i^(th) time period (e.g., for five time periods,i=1, 2, . . . , 5) of a given moment n may be calculated. For the firstthree moments (n=1, 2, 3), the following set of equations provide thisnormalized difference:S _(i) =|A ₀ −M ₀ ^(i) |/A ₀T _(i) =|A ₁ −M ₁ ^(i) |/A ₁U _(i) =|A ₂ −M ₂ ^(i) |/A ₂where the S_(i), T_(i), and U_(i) values are set to zero when thecorresponding one of A₀, A₁, or A₂ are zero.

Confirmation of pacing capture may be detected based on the S_(i),T_(i), and U_(i) values. For example, pacing capture over ipredetermined time periods can be confirmed if for each non-zero valueof A_(n), its corresponding S_(i), T_(i), or U_(i) value is less than apredetermined threshold or set of threshold values. For example, thisthreshold for the moment M₀ can be in the range between 0 and 0.1. Asmall deviation of the moment M_(n) ^(i) from the corresponding meanvalue indicates that the time-behavior of the ECG signal (viewed as afunction of time) is morphologically consistent over successive pacingperiods, thereby demonstrating pacing capture. In some embodiments, thisthreshold can be defined by a user, e.g., via input (816) provided by auser interface (e.g., of input/output device (127)). If pacing captureis confirmed (822), then this can be indicated, e.g., on a userinterface by highlighting a “Pacing Capture Confirmed” indicator.

As described above with reference to FIG. 7, if no ectopic beat activityis detected, and pacing capture is confirmed, then an ablation deviceand processor(s) associated therewith (e.g., pulse generation controller(907) and other devices described herein) can be set to deliver pulsedelectric field ablation. If ectopic beat activity is detected and/orpacing capture is not confirmed, then the ablation device and/orassociated processor(s) can be deactivated and/or not set to deliverypulsed electric field ablation, for example, by activation of a suitablerelay that disconnects the ablation device from the ablation generator.Specifically, if ectopic beat activity is detected, then it would beundesirable to deliver pulsed electric field ablation because it cancause fibrillation.

In some embodiments, hierarchical voltage pulse waveforms having anested structure and a hierarchy of time intervals as described hereinmay be useful for irreversible electroporation, providing control andselectivity in different tissue types. FIG. 8 is a flowchart (600) of anembodiment of a tissue ablation process. The method (600) includes theintroduction of a device (e.g., ablation device (110, 220)) into anendocardial space, e.g., of a left atrium, at (602). The ablation devicemay be advanced to be disposed in a pulmonary vein ostium, at (604). Inembodiments where the device may include a first and secondconfiguration (e.g., compact and expanded), the device may be introducedin the first configuration and transformed to a second configuration tocontact tissue at or near the pulmonary vein antrum or ostium, at (606),with further descriptions of suitable ablation devices provided inInternational Application No. PCT/US2019/014226. The ablation device mayinclude electrodes and may be configured in anode-cathode subsets, at(608), as discussed in detail above. For example, a subset of electrodesof the devices may be selected as anodes, while another subset ofelectrodes of the device may be selected as cathodes, with the voltagepulse waveform applied between the anodes and cathodes.

A pulse waveform may be generated by a signal generator (e.g., signalgenerator (122)) and may include a plurality of levels in a hierarchy,at (610). A variety of hierarchical waveforms may be generated with asignal generator as disclosed herein. For example, the pulse waveformmay include a first level of a hierarchy of the pulse waveform includinga first set of pulses. Each pulse has a pulse time duration and a firsttime interval separating successive pulses. A second level of thehierarchy of the pulse waveform may include a plurality of first sets ofpulses as a second set of pulses. A second time interval may separatesuccessive first sets of pulses. The second time interval may be atleast three times the duration of the first time interval. A third levelof the hierarchy of the pulse waveform may include a plurality of secondsets of pulses as a third set of pulses. A third time interval mayseparate successive second sets of pulses. The third time interval maybe at least thirty times the duration of the second level time interval.The pulse waveform generated by the signal generator may be delivered totissue using the ablation device, at (612). As described herein, ifectopic beat activity is detected or pacing capture is not confirmed,then the delivery of pulse waveform activity may be interrupted, e.g.,at (608) or (610). Examples of pulse waveforms that can be used with theablation devices described herein are provided in InternationalApplication No. PCT/US2016/57664, filed on Oct. 19, 2016, titled“Systems, apparatuses and methods for delivery of ablative energy totissue,” incorporated herein by reference in its entirety.

It is understood that while the examples herein identify separatemonophasic and biphasic waveforms, it should be appreciated thatcombination waveforms, where some portions of the waveform hierarchy aremonophasic while other portions are biphasic, may also be generated. Avoltage pulse waveform having a hierarchical structure may be appliedacross different anode-cathode subsets (optionally with a time delay).As discussed above, one or more of the waveforms applied across theanode-cathode subsets may be applied during the refractory period of acardiac cycle. The pulse waveform may be delivered to tissue. It shouldbe appreciated that the steps described in certain figures may becombined and modified as appropriate.

It should be understood that the examples and illustrations in thisdisclosure serve exemplary purposes and departures and variations suchas numbers of splines, number of electrodes, and so on can be built anddeployed according to the teachings herein without departing from thescope of this invention. While specific parameters such as samplingfrequency, time intervals and so on were given for exemplary purposesonly in the description herein, it should be understood that othervalues of the various parameters can be used as convenient for theapplication by those skilled in the art based on the teachings presentedin this disclosure.

As used herein, the terms “about” and/or “approximately” when used inconjunction with numerical values and/or ranges generally refer to thosenumerical values and/or ranges near to a recited numerical value and/orrange. In some instances, the terms “about” and “approximately” may meanwithin ±10% of the recited value. For example, in some instances, “about100 [units]” may mean within ±10% of 100 (e.g., from 90 to 110). Theterms “about” and “approximately” may be used interchangeably.

Some embodiments described herein relate to a computer storage productwith a non-transitory computer-readable medium (also may be referred toas a non-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also may be referred to as code oralgorithm) may be those designed and constructed for the specificpurpose or purposes. Examples of non-transitory computer-readable mediainclude, but are not limited to, magnetic storage media such as harddisks, floppy disks, and magnetic tape; optical storage media such asCompact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read OnlyMemories (CD-ROMs), and holographic devices; magneto-optical storagemedia such as optical disks; carrier wave signal processing modules; andhardware devices that are specially configured to store and executeprogram code, such as Application-Specific Integrated Circuits (ASICs),Programmable Logic Devices (PLDs), Read-Only Memory (ROM) andRandom-Access Memory (RAM) devices. Other embodiments described hereinrelate to a computer program product, which may include, for example,the instructions and/or computer code disclosed herein.

The systems, devices, and/or methods described herein may be performedby software (executed on hardware), hardware, or a combination thereof.Hardware modules may include, for example, a general-purpose processor(or microprocessor or microcontroller), a field programmable gate array(FPGA), and/or an application specific integrated circuit (ASIC).Software modules (executed on hardware) may be expressed in a variety ofsoftware languages (e.g., computer code), including C, C++, Java®, Ruby,Visual Basic®, and/or other object-oriented, procedural, or otherprogramming language and development tools. Examples of computer codeinclude, but are not limited to, micro-code or micro-instructions,machine instructions, such as produced by a compiler, code used toproduce a web service, and files containing higher-level instructionsthat are executed by a computer using an interpreter. Additionalexamples of computer code include, but are not limited to, controlsignals, encrypted code, and compressed code.

The specific examples and descriptions herein are exemplary in natureand embodiments may be developed by those skilled in the art based onthe material taught herein without departing from the scope of thepresent invention.

The invention claimed is:
 1. A system, comprising: a first controllerconfigured to generate a pulsed waveform and deliver the pulsed waveformin synchrony with a set of pacing pulses to an ablation device; and asecond controller configured to: generate the set of pacing pulses anddeliver the set of pacing pulses to a pacing device for cardiacstimulation of a heart; receive cardiac signal data of the heart;confirm pacing capture of the heart based on the cardiac signal data;monitor for ectopic activity of the heart by analyzing frequencycomponents associated with the cardiac signal data; and generate andsend a set of signals to the first controller based on the confirmingand the monitoring.
 2. The system of claim 1, wherein the secondcontroller is configured to monitor for ectopic activity by: extractingsliding windows of the cardiac signal data following delivery of eachpacing pulse from the set of pacing pulses; performing discrete Fouriertransforms of the sliding windows to obtain frequency components of thesliding windows; identifying peak frequencies over a subrange offrequencies in the frequency components of the sliding windows; anddetermining whether there is ectopic activity based on analyzing thepeak frequencies.
 3. The system of claim 2, wherein the secondcontroller is configured to determine whether there is ectopic activityby, for each sliding window: calculating a ratio of an amplitude of thepeak frequency for that sliding window to a maximum amplitude offrequencies up to the Nyquist frequency of the frequency components ofthat sliding window; and determining whether the ratio is greater than athreshold value.
 4. The system of claim 1, wherein the second controlleris configured to confirm pacing capture by: extracting portions of thecardiac signal data following delivery of a subset of successive pacingpulses from the set of pacing pulses; calculating, for each extractedportion, a set of moments of a function associated with that extractedportion; and confirming pacing capture of the set of pacing pulses basedat least on the set of moments calculated for each extracted portion. 5.The system of claim 4, wherein each extracted portion of the cardiacsignal data includes cardiac signal data within a predetermined timeinterval following an onset of a pacing pulse from the subset ofsuccessive pacing pulses.
 6. The system of claim 1, further comprisingthe pacing device, the pacing device including a first set of electrodesfor cardiac stimulation of the heart and a second set of electrodes forcapturing the cardiac signal data.
 7. The system of claim 1, furthercomprising the ablation device, the ablation device including a set ofelectrodes for generating a pulsed electric field to ablate cardiactissue in response to receiving the pulsed waveform.
 8. The system ofclaim 1, wherein the set of signals includes a signal indicating pacingcapture, the second controller configured to generate and send thesignal indicating pacing capture in response to confirming pacingcapture.
 9. The system of claim 8, wherein the set of signals includes asignal indicating ectopic activity, the second controller configured togenerate and send the signal indicating ectopic activity in response todetecting ectopic activity based on the monitoring.
 10. An apparatus,comprising: a memory; and a processor operatively coupled to the memory,the processor configured to: extract portions of cardiac signal datafollowing delivery of a set of successive pacing pulses to a heart;calculate, for each extracted portion, a set of moments of a functionassociated with that extracted portion; confirm pacing capture of theheart based at least on the set of moments calculated for each extractedportion; and in response to confirming pacing capture, generate and senda signal indicating pacing capture to a signal generator configured togenerate pulsed waveforms for cardiac ablation such that the signalgenerator, in response to receiving the signal, is activated forgenerating the pulsed waveforms.
 11. The apparatus of claim 10, whereineach extracted portion of the cardiac signal data includes cardiacsignal data within a predetermined time interval following an onset of apacing pulse from the subset of successive pacing pulses.
 12. Theapparatus of claim 11, wherein the predetermined time interval isbetween about 5 milliseconds and about 50 milliseconds.
 13. Theapparatus of claim 10, wherein the processor is configured to confirmpacing capture by: calculating, for each moment from the set of moments,an average value of that moment by averaging values of the momentscalculated for the extracted portions; calculating, for each moment fromthe set of moments, a normalized difference between the average value ofthat moment and the value of that moment calculated for each extractedportion; and confirming pacing capture based on the normalizeddifferences calculated for each moment from the set of moments.
 14. Theapparatus of claim 10, wherein the processor is configured to confirmpacing capture by: calculating average values of each of the set ofmoments; calculating normalized differences between the average valuesof each of the set of moments and values of the moments calculated forthe extracted portions; and determining when each normalized differenceis less than a respective predetermined threshold.
 15. The apparatus ofclaim 10, wherein the processor is further configured to: analyze localpeak frequencies of the cardiac signal data to detect ectopic activityof the heart; and in response to detecting ectopic activity, generateand send a signal indicating ectopic activity to the signal generatorsuch that the signal generator, in response to receiving the signalindicating ectopic activity, is deactivated from generating the pulsedwaveforms.
 16. The apparatus of claim 15, wherein the processor isconfigured to analyze the local peak frequencies of the cardiac signaldata to detect ectopic activity by: extracting sliding windows of thecardiac signal data; performing discrete Fourier transforms of theextracted sliding windows and applying a filter to the resultingdiscrete Fourier transforms to produce filtered frequency outputs of theextracted sliding windows; identifying the local peak frequencies in thefiltered frequency outputs; and detecting ectopic activity based atleast on values of the peak frequencies in the filtered frequencyoutputs.
 17. An apparatus, comprising: a memory; and a processoroperatively coupled to the memory, the processor configured to: extracta sliding window of cardiac signal data of a heart; perform a transformof the sliding window to obtain frequency components of the data over arange of frequencies; identify a peak frequency over a subrange of therange of frequencies, the peak frequency having a value that is greaterthan that of the remaining frequencies in the subrange of frequencies;detect ectopic activity of the heart based on a comparison between arelative measure of the value of the peak frequency to a maximum valueover the range of frequencies and a predetermined value; and in responseto detecting ectopic activity, generate and send a signal indicatingectopic activity to a signal generator configured to generate pulsedwaveforms for cardiac ablation such that the signal generator, inresponse to receiving the signal, interrupts generation of the pulsewaveforms.
 18. The apparatus of claim 17, wherein the transform is adiscrete Fourier transform.
 19. The apparatus of claim 17, wherein theprocessor is configured to detect ectopic activity by: calculating aratio of the value of the peak frequency to the maximum value; anddetermining that the ratio is greater than the predetermined value. 20.The apparatus of claim 19, wherein the predetermined value is betweenabout 0.01 and about 0.25.
 21. The apparatus of claim 19, wherein thepredetermined value is between about 0.01 and about 0.15.
 22. Theapparatus of claim 17, wherein the processor is operatively coupled to auser interface, and the predetermined value is set by a user via theuser interface.
 23. A method, comprising: extracting, by a processor, asliding window of cardiac signal data of a heart; performing, by theprocessor, a transform of the sliding window to obtain frequencycomponents of the data over a range of frequencies; identifying, by theprocessor, a peak frequency over a subrange of the range of frequencies,the peak frequency having a value that is greater than that of theremaining frequencies in the subrange of frequencies; detecting, by theprocessor, ectopic activity of the heart based on a comparison between arelative measure of the value of the peak frequency to a maximum valueover the range of frequencies and a predetermined value; and in responseto detecting ectopic activity, generating and sending, by the processor,a signal indicating ectopic activity to a signal generator configured togenerate pulsed waveforms for cardiac ablation such that the signalgenerator, in response to receiving the signal, interrupts generation ofthe pulse waveforms.
 24. The method of claim 23, wherein the transformis a discrete Fourier transform.
 25. The method of claim 23, wherein thedetecting the ectopic activity includes: calculating a ratio of thevalue of the peak frequency to the maximum value; and determining thatthe ratio is greater than the predetermined value.
 26. The method ofclaim 25, wherein the predetermined value is between about 0.01 andabout 0.25.
 27. The method of claim 25, wherein the predetermined valueis between about 0.01 and about 0.15.